Cardiovascular disease remains a worldwide public health concern, despite decades of research and the availability of numerous targeted therapies. While the intrinsic physiological mechanisms regulating cardiovascular function are similar between males and females, marked sex differences are established in terms of cardiovascular disease onset, pathophysiology, manifestation, susceptibility, prevalence, treatment responses and outcomes in animal models and clinical populations. Premenopausal females are generally protected from cardiovascular disease when compared to men of similar age, and tend to develop cardiovascular complications later in life following menopause. Emerging evidence suggests this cardioprotection in females is, in part, attributed to sex differences in hormonal regulators such as the renin-angiotensin system. To date, research has largely focused on canonical renin-angiotensin system pathways, and shown that premenopausal females are protected from cardiovascular derangements produced by activation of angiotensin II pathways. More recently, a vasodilatory arm of the renin-angiotensin system has emerged that is characterized by angiotensin-(1-7), angiotensin-converting enzyme 2, and Mas receptors. Emerging studies provide evidence for a shift towards these cardioprotective angiotensin-(1-7) pathways in females, with effects modulated by interactions with estrogen. Despite well-established sex differences, female comparison studies on cardiovascular outcomes are lacking at both the preclinical and clinical levels. Furthermore, there are no specific guidelines in place for treatment of cardiovascular disease in men versus women, including for therapies targeting the renin-angiotensin system. This review summarizes current knowledge of sex differences in cardiovascular actions of the renin-angiotensin system, focusing on interactions with gonadal hormones, emerging data for protective angiotensin-(1-7) pathways, and potential clinical implications for established and novel therapies.Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1

Obesity is a chronic state of energy imbalance that represents a major public health problem and greatly increases the risk for developing hypertension, hyperglycemia, and a multitude of related pathologies that encompass the metabolic syndrome. The underlying mechanisms and optimal treatment strategies for obesity, however, are still not fully understood. The control of energy balance involves the actions of circulating hormones on a widely distributed network of brain regions involved in the regulation of food intake and energy expenditure, including the arcuate nucleus of the hypothalamus. While obesity is known to disrupt neurocircuits controlling energy balance, including those in the hypothalamic arcuate nucleus, the pharmacological targeting of these central mechanisms often produces adverse cardiovascular and other off-target effects. This highlights the critical need to identify new anti-obesity drugs that can activate central neurocircuits to induce weight loss without negatively impacting blood pressure control. The renin–angiotensin system may provide this ideal target, as recent studies show this hormonal system can engage neurocircuits originating in the arcuate nucleus to improve energy balance without elevating blood pressure in animal models. This review will summarize the current knowledge of renin–angiotensin system actions within the arcuate nucleus for control of energy balance, with a focus on emerging roles for angiotensin II, prorenin, and angiotensin-(1–7) pathways.

Angiotensin (Ang)‐(1‐7), a protective hormone of the renin‐angiotensin system, has emerged as a novel target to improve cardiovascular and metabolic functions in animal models. In addition to blood pressure lowering effects, recent studies from our laboratory and others have shown that Ang‐(1‐7) can promote insulin sensitization and weight loss in obese rodents. Our recent preliminary findings suggest these effects are centrally‐mediated, with Ang‐(1‐7) mas receptors (MasR) widely distributed to the arcuate nucleus of the hypothalamus. In particular, we found that MasR are highly colocalized with proopiomelanocortin (POMC)‐containing neurons in this brain region, neurons which when activated reduce food intake and increase energy expenditure to promote weight loss as well as improve insulin sensitivity. The importance of MasR localized to POMC neurons in metabolic functions, however, is currently unknown. In this study, we tested the hypothesis MasR expressed in POMC neurons are important for normal control of energy balance and glucose homeostasis. To test this, mice containing conditional knockout alleles of the Ang‐(1‐7) MasR were crossed with POMC‐Cre mice to specifically delete MasR from POMC neurons (POMCMasR‐KO). Body mass and composition, insulin sensitivity, and glucose tolerance were measured in male and female POMCMasR‐KO mice and wild‐type littermates (n=6‐11/group) at 8 weeks of age on a standard chow diet. Despite similar fasting glucose and insulin levels, male POMCMasR‐KO mice had worsened insulin sensitivity compared with wild‐type littermates (area under the curve for decrease in glucose from baseline in response to intraperitoneal insulin: ‐2134±1071 vs. ‐6531±1507, respectively; p=0.029), with no differences in body mass, adiposity, lean mass, or glucose tolerance. In female mice, there was no effect of POMC MasR deletion on any of the metabolic outcomes tested. These findings suggest that MasR localized to POMC neurons provide tonic and sex‐specific modulation of insulin sensitivity in mice. Additional studies are needed to determine if altered MasR signaling in POMC neurons could contribute to insulin resistance in disease states such as obesity and type II diabetes.